The present invention relates generally to a) implantable drug delivery devices, b) medical treatment methods and c) experimental animal models useable in biomedical research. More particularly, the present invention relates to new methods of preparing implantable substance delivery pellets and to the use of such pellets to deliver therapeutic agents, biological factors, gene therapy preparations, and other substances for therapeutic purposes or to induce a disease or disorder in laboratory animals.
Implantable Substance Delivery Systems
Implantable drug delivery devices have heretofore been known in the art. Such implantable drug delivery devices include pellets, capsules and rods made of porous polymeric material that contains the drug that is to be administered. The device is surgically implanted in the body of a human or veterinary patient and the drug then escapes from the device through pores in the polymer. These types of implantable drug delivery apparatus are particularly useable for delivering drugs at sustained rates over extended periods of time. Examples of drug delivery implants of this type include Norplant(copyright), Lupron Depot(copyright) drug-delivery system (TAP Pharmaceutical Products Inc.; Lake Forest, Ill.) and Gliadel Wafer(copyright) (Guilford Pharmaceuticals Inc.; Baltimore, Md.).
Use of Implantable Substance Delivery Devices In Animal Models of Disease:
Implantable delivery devices may also be used to deliver bioactive compounds that will induce or mimic a certain disease or disorder in laboratory animals. In one such laboratory animal model, pellets made of polymethylmethacrylate (Hydron NCC non-adhesive cell culture media, from Hydro Med Sciences, 8 Cedar Brook Drive, Cranbury, N.J. 08512333) were prepared to contain substance(s) known to cause retinal neovascularization (e.g., VEGF and/or basic-FGF) and were implanted intravitreally in the eyes of alaboratory animals in an effort to induce experimental retinal neovascularization in the animals. An example of this has been reported in Ozaki, H. et al., Intravitreal Sustained Release VEGF Causes Retinal Neovascularization in Rabbits and Breakdown of the Blood-Retinal Barrier in Rabbits and Primates, Exp. Eye Res. 64:505-517 (1997). However, the materials and methods by which such delivery devices were prepared is less than optimal for all applications or for routine usage of the technique as an animal model for retinal neovascularization in ophthalmologic experimentation. For example, the method of Ozaki et al. does not cause robust neovascularization to occur in subject test animals. In particular, onset of neovascularization does not occur for 2-3 weeks after the implantation procedure. In addition, the neovascularization effect is mild and has a very short lived and reversible effect. Therefore, it is desirable to develop improved materials and methods whereby such implantable devices may be prepared containing not only VEGF, but other factors known to play a role in inducing neovascularization (e.g., basic fibroblast growth factor (bFGF)), or for providing more highly effectctive, sustained delivery of other substances, proteins or therapeutic agents.
New animal models that involve delivery of bological factors that cause neovascularazation (VEGF and/or bFGF) into the eyes of experimental animals are worthy of investigation in view of the seriousness of some of the ophthalmological diseases and disorders characterized by neovascularization. Among these diseases and disorders are diabetic retinopathy and age related macular degeneration (AMD).
Diabetic Retinopathy:
Two main types of diabetic retinopathy are known to occur. The first, xe2x80x9cbackground diabetic retinopathyxe2x80x9d or xe2x80x9cnon-proliferative retinopathy,xe2x80x9d typically occurs in the earlier stages of diabetic disease. Background diabetic retinopathy is characterized by damage to small retinal blood vessels, causing them to leak blood or fluid into the retina. The loss of vision that occurs as a result of background diabetic retinopathy is typically due to the accumulation of fluid in the central area of the retina, known as the macula. This accumulation of fluid is called macular edema, and can cause temporary or permanent decreased vision.
The second type of diabetic retinopathy is called xe2x80x9cproliferative diabetic retinopathy.xe2x80x9d Proliferative diabetic retinopathy is the end result of the closure or occlusion of many small retinal blood vessels. The retinal tissue, which depends on those vessels for oxygen and nutrition, ceases to function properly and the areas of the retina in which the blood vessels have closed then foster the growth of many new abnormal new blood vessels. This neovascularization process can be very damaging because it can cause intravitreal hemorrhage, formation of retinal scar tissue, retinal detachment and/or glaucoma, any of which can cause substantial vision loss or even blindness.
Diabetic retinopathy can occur in both Type I diabetics (onset of diabetes prior to age 40) and Type II diabetics (onset after age 40), although it tends to be more common and more severe in Type I patients. Because Type II diabetes is often not diagnosed until the patient has had the disease for many years, diabetic retinopathy may be present in a Type II patient at the time diabetes is discovered. In fact, many patients first learn that they have diabetes when their ophthalmologist finds diabetic retinopathy on a routine eye exam.
The duration of diabetes is important in the development of diabetic retinopathy. The longer a patient has had diabetes, the more likely they are to have diabetic retinopathy. Diabetic retinopathy does not usually occur for at least 3 years after the onset of Type I diabetes. After having diabetes for 15 years, however, about 80% of type I diabetics will have some degree of diabetic retinopathy, and 50% will have proliferative retinopathy.
The diagnosis of diabetic retinopathy is made based on the appearance of the retina as seen on a dilated retinal examination. Significant vision-threatening diabetic retinopathy can be present even if you have no visual symptoms. Retinal photographs and fluorescein angiography are also used to diagnose and document progression of diabetic retinopathy. Fluorescein angiography is a technique which involves injecting a dye (fluorescein) into the veins and taking a series of photographs of the retina while the dye circulates through the retinal vessels. This angiography is used to determine which retinal vessels are leaking, and helps direct laser treatment more precisely.
The treatment of diabetic retinopathy in any particular case depends upon multiple factors, including the type and degree of retinopathy, associated ocular factors such as cataract or vitreous hemorrhage, and the medical history of the patient. Treatment options include laser photocoagulation, cryotherapy (freezing), and vitrectomy surgery (removal of the vitreous gel along with blood, scar tissue, etc.)
Age Related Macular Degeneration:
Age-related macular degeneration (AMD) is the largest cause of severe and permanent vision loss in the western world. AMD is primarily an age related disease process although certain individuals are believed to be genetically predisposed to the disease and chronic sunlight exposure and poor nutrition may also be predisposing factors. AMD most commonly occurs after 50 years of age and its occurrence increases in frequency as the population ages.
There are two basic types of age-related macular degenerationxe2x80x94dry and wet. In dry macular degeneration, aging yellow spots called xe2x80x9cdrusenxe2x80x9d are present with or without atrophy of the macula. In this dry form of the disease, the ptient""s visual acuity is usually not drastically affected. In the wet form of the disease, abnormal blood vessels grow behind the retina in the subretinal space and leakage of blood and fluid occurs (hence the name xe2x80x9cwetxe2x80x9d). With time, the abnormal blood vessels proliferate and grow into a scar. Once a scar has formed, the condition is no longer treatable. Only about 10-20% of AMD patients have the wet form of the disease, but the wet form of the disease is responsible for approximately 90% of severe vision loss from AMD.
The present invention provides new and improved methods for preparing and using substance delivery devices for sustained delivery of substances into a human or animal body. In many instances, the present methods provide substantial benefits. For example, the implantable substance delivery devices of the present invention provide sustained and effective delivery of substances to tissues adjacent the location at which the devices are implanted.
In accordance with the present invention, there is provided methods for preparing an implantable device for a sustained delivery of a substance within a body of a human or animal subject are featured. In these methods, a biocompatible polymer is dissolved in a suitable solvent solution to produce a polymer-solvent solution admixture. Further, a substance is added to the polymer-solvent solution admixture. Still further, the polymer-solvent solution-substance is dried to form a substantially dry mass. The substantially dry mass is refrigerated. In one embodiment, after forming the substantially dry mass and before refrigerating the mass, a liquid is added to the substantially dry mass causing the mass to soften and the softened mass may be manipulated to a desired shape. In one embodiment, a second polymer-solvent solution-substance admixture may be added to the substantially dry mass. This second polymer-solvent solution-substance admixture is allowed to dry. This second polymer-solvent solution-substance admixture may be prepared in the same manner as the afore described polymer-solvent solution-substance admixture. The second polymer-solvent solution-substance admixture may be added to the substantially dry mass before the steps of adding a liquid, manipulating and refrigerating of the mass.
Further in accordance with the present invention, methods for preparing an implantable device for a sustained delivery of a substance within a body of a human or animal subject are featured. In these methods, a biocompatible polymer is dissolved in a suitable solvent solution to produce a polymer-solvent solution admixture. Further, a substance is added to the polymer-solvent solution admixture. Still further, the polymer-solvent solution-substance is dried to form a substantially dry mass. A liquid is then added to the substantially dry mass causing the mass to soften and the softened mass is manipulated to a desired shape. In one embodiment, the manipulated mass may be refrigerated. In one embodiment, a second polymer-solvent solution-substance admixture may be added to the substantially dry mass. This second polymer-solvent solution-substance admixture is allowed to dry. This second polymer-solvent solution-substance admixture may be prepared in the same fashion as the afore described polymer-solvent solution-substance admixture. The second polymer-solvent solution-substance admixture may be added to the substantially dry mass before the steps of adding a liquid, manipulating and refrigerating of the mass.
Still further in accordance with the present invention, methods for preparing an implantable device for a sustained delivery of a substance within a body of a human or animal subject are featured. In these methods, a biocompatible polymer is dissolved in a suitable solvent solution to produce a polymer-solvent solution admixture. Further, a substance is added to the polymer-solvent solution admixture. Still further, the polymer-solvent solution-substance is dried to form a substantially dry mass. Still further, a second polymer-solvent solution-substance admixture is added to the substantially dry mass. This second polymer-solvent solution-substance admixture is allowed to dry. This second polymer-solvent solution-substance admixture is prepared in the same fashion as the afore described polymer-solvent solution-substance admixture. In one embodiment, a liquid may be added to the substantially dry mass causing the mass to soften and the softened mass may be manipulated to a desired shape. In one embodiment, the substantially dry mass may be refrigerated.
Still further in accordance with the invention, the polymers may be non-biodegradable. For example, Hydron (polymethylmethacrylate available commercially as xe2x80x9cHydron NCCxe2x80x9d non-adhesive cell culture media, from Hydro Med Sciences, 8 Cedar Brook Drive, Cranbury, N.J. 08512333), polyester, polycarbonate, polysulfone, polyvinyl chloride, polyethylene, polypropylene, poly(N-vinyl pyrrolidone), poly(methyl methacrylate), poly(vinyl alcohol), poly(acrylic acid), polyacrylamide, poly(ethylene-co-vinyl acetate), poly(methacrylic acid), mixtures thereof and combinations thereof may be used.
Still further in accordance with the invention, the polymers may be biodegradable. For example, poly (ethylene glycol), polyvinylpyrrolidine, polylactides (PLA), polyglycolides (PGA), poly(lactide-co-glycolides) (PLGA), polyanhydrides, polyorthoesters, poly(DTH iminocarbonate) poly(bisphenol A iminocarbonate) polycyanoacrylate, polyphosphazene, mixtures thereof and combinations thereof may be used in accordance with the invention.
Still further in accordance with the invention, the solvent solution may comprise an organic solvent. For example, the organic solvent may be ethanol. Ethanol may be used at a concentration of, for example, about 70 to about 95% .
Still further in accordance with the invention, the substance may be a chemical, a therapeutic agent, a biomolecule, a therapeutic biomolecule, an anti-inflammatory agent, an antineoplastic agent, a protein, a steroid, a hormone, a RNA, a DNA, a combination of a RNA and a DNA, an antisense oligonucleotide sequence, an antisense oligoribonucleotide sequence, a combination of an antisense oligonucleotide sequence and an antisense oligoribonucleotide sequence, an antisense oligonucleotide sequence to a focal adhesion kinase RNA, an antisense oligoribonucleotide sequence to a focal adhesion kinase RNA, a combination of an antisense oligonucleotide sequence and an antisense oligoribonucleotide sequence to a focal adhesion kinase RNA, an antisense oligonucleotide sequence to a focal adhesion kinase gene, an antisense oligoribonucleotide sequence to a focal adhesion kinase gene, a combination of an antisense oligonucleotide sequence and an antisense oligoribonucleotide sequence to a focal adhesion kinase gene, VEGF and bFGF.
Still further in accordance with the invention, is a method of using the implantable device by introducing the device into a body of a human or animal subject such that the substance may be released from the device. For example, the device may be implanted into an eye, into the vitreous of an eye by surgical means and into the subchoroidal space where a sclera is cut to expose a choroidae.
Still further in accordance with the invention, is a method where introducing the device into a body of a subject causes a therapeutic benefit to occur.
Still further in accordance with the invention, is a method where a desired disease or disorder is caused in an animal by introducing the device into a body of the animal. For example, the disease or disorder may be neovascularization and/or age-related macular degeneration.
Still further in accordance with the invention, are implantable devices prepared for a sustained delivery of a substance within a body of a human or animal subject made by the afore described methods.
Any feature or combination of features described herein are included within the scope of the present invention provided that the features included in any such combination are not mutually inconsistent as will be apparent from the context, this specification, and the knowledge of one of ordinary skill in the art.
Additional advantages and aspects of the present invention are apparent in the following detailed description and claims.